1-25563141-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015627.3(LDLRAP1):c.604T>C(p.Ser202Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,611,136 control chromosomes in the GnomAD database, including 218,659 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S202H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.48 ( 17958 hom., cov: 31)

Exomes 𝑓: 0.52 ( 200701 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.666

Publications

51 publications found

Variant links:

Genes affected

LDLRAP1 (HGNC:18640): (low density lipoprotein receptor adaptor protein 1) The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]

LDLRAP1 Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLRAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.5136673E-5).

BP6

Variant 1-25563141-T-C is Benign according to our data. Variant chr1-25563141-T-C is described in ClinVar as Benign. ClinVar VariationId is 296982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLRAP1	NM_015627.3 link	c.604T>C	p.Ser202Pro	missense_variant	Exon 6 of 9	ENST00000374338.5	NP_056442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLRAP1	ENST00000374338.5 link	c.604T>C	p.Ser202Pro	missense_variant	Exon 6 of 9	1	NM_015627.3	ENSP00000363458.4

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72733

AN:

151808

Hom.:

17949

Cov.:

show subpopulations

Gnomad AFR

AF:

0.354

Gnomad AMI

AF:

0.490

Gnomad AMR

AF:

0.520

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.445

Gnomad FIN

AF:

0.500

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.538

Gnomad OTH

AF:

0.525

GnomAD2 exomes

AF:

0.505

AC:

126613

AN:

250530

AF XY:

0.506

show subpopulations

Gnomad AFR exome

AF:

0.351

Gnomad AMR exome

AF:

0.552

Gnomad ASJ exome

AF:

0.581

Gnomad EAS exome

AF:

0.448

Gnomad FIN exome

AF:

0.504

Gnomad NFE exome

AF:

0.534

Gnomad OTH exome

AF:

0.537

GnomAD4 exome

AF:

0.522

AC:

762025

AN:

1459208

Hom.:

200701

Cov.:

AF XY:

0.521

AC XY:

378270

AN XY:

726082

show subpopulations

African (AFR)

AF:

0.355

AC:

11858

AN:

33432

American (AMR)

AF:

0.547

AC:

24449

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.587

AC:

15329

AN:

26100

East Asian (EAS)

AF:

0.500

AC:

19827

AN:

39670

South Asian (SAS)

AF:

0.435

AC:

37478

AN:

86192

European-Finnish (FIN)

AF:

0.496

AC:

26476

AN:

53372

Middle Eastern (MID)

AF:

0.566

AC:

3259

AN:

5756

European-Non Finnish (NFE)

AF:

0.534

AC:

592471

AN:

1109680

Other (OTH)

AF:

0.512

AC:

30878

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

17399

34798

52198

69597

86996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16810

33620

50430

67240

84050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.479

AC:

72780

AN:

151928

Hom.:

17958

Cov.:

AF XY:

0.476

AC XY:

35369

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.354

AC:

14675

AN:

41436

American (AMR)

AF:

0.521

AC:

7948

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.586

AC:

2034

AN:

3472

East Asian (EAS)

AF:

0.475

AC:

2454

AN:

5166

South Asian (SAS)

AF:

0.446

AC:

2144

AN:

4808

European-Finnish (FIN)

AF:

0.500

AC:

5278

AN:

10556

Middle Eastern (MID)

AF:

0.562

AC:

164

AN:

292

European-Non Finnish (NFE)

AF:

0.538

AC:

36532

AN:

67912

Other (OTH)

AF:

0.523

AC:

1104

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1894

3788

5681

7575

9469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.516

Hom.:

76770

Bravo

AF:

0.477

TwinsUK

AF:

0.546

AC:

2025

ALSPAC

AF:

0.539

AC:

2078

ESP6500AA

AF:

0.345

AC:

1519

ESP6500EA

AF:

0.533

AC:

4583

ExAC

AF:

0.499

AC:

60644

Asia WGS

AF:

0.427

AC:

1485

AN:

3478

EpiCase

AF:

0.546

EpiControl

AF:

0.537

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 4

Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jun 30, 2022

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 13, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLRAP1 c.604T>C (p.Ser202Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.51 in 250530 control chromosomes, therefore suggesting the variant is the major allele. Two ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

Sep 28, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Cardiovascular phenotype

Benign:1

Nov 02, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Familial hypercholesterolemia

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

4.9

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.27

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.22

MetaRNN

Benign

0.000025

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

PhyloP100

-0.67

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.76

REVEL

Benign

0.041

Sift

Benign

0.14

Sift4G

Benign

0.16

Vest4

0.069

ClinPred

0.0090

GERP RS

-2.4

Varity_R

0.073

gMVP

0.24

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over